Spatially and Functionally Distinct mTORC1 Entities Orchestrate the Cellular Response to Amino Acid Availability

• DOI: 10.1101/2023.10.03.559930
• Publication Date: 2023-10-03T22:05:18Z
• Authors: Stephanie A. Fern...; Danai-Dimitra Ang...; Julian Nüchel; Jiyoung Pan; Peter Gollwitzer; Yoav Elkis; Filippo Artoni; Sabine Wilhelm; Marija Kovacevic-...; Constantinos Deme...

Abstract Amino acid (AA) availability is a robust determinant of cell growth, through controlling mTORC1 activity 1 . According to the predominant model in field, AA sufficiency drives recruitment and activation on lysosomal surface by heterodimeric Rag GTPases, from where it coordinates majority cellular processes (reviewed 2,3 ). Importantly, however, 15 years after its initial discovery, teleonomy proposed regulation mTORC1, acts effector proteins remain enigmatic 4 Here, using multiple pharmacological genetic means perturb sensing protein recycling machineries, we describe spatial separation downstream functions mammalian cells, with non-lysosomal phosphorylating distinct substrates response different sources. Moreover, reveal that fraction mTOR localizes at lysosomes due basal proteolysis locally supplies new AAs, even cells grown presence extracellular nutrients, whereas cytoplasmic regulated exogenous AAs. Overall, our study substantially expands knowledge about topology hints existence distinct, Rag- lysosome-independent mechanisms control other subcellular locations. Given importance signalling for human ageing disease 2 , findings will likely open directions toward identification function-specific regulators, suggest targets drug discovery against conditions dysregulated future.